Immunomodulation of malignant melanoma by contact sensitizing agents

Abstract

The importance of host defense against malignant melanoma is underlined by the use of immunomodulating agents as effective therapies. Diphencyprone and 2,4-dinitrochlorobenzene (DNCB) have been used successfully as contact sensitizing agents in this regard. Through haptenation of cell surface and cytoplasmic proteins, these agents trigger a CD8⁺ T-lymphocyte predominant allergic contact hypersensitivity response. Th17 cells may also play a critical role. The effectiveness of these agents at stimulating tumor defense may be limited to melanoma of the skin. Response to immunotherapy using diphencyprone and DNCB is governed by the immune status of the host, which is affected by tumor burden, UV light and age. Additionally, diphencyprone and DNCB elicit synergy with other methods of treatment and thus may be used as adjuncts. Two current prospective trials may aid in elucidating the impact that this treatment modality has on the prognosis and quality of life of patients with melanoma.

Keywords::

• 2,4-dinitrochlorobenzene
• allergic contact hypersensitivity
• CD8⁺ T-lymphocytes
• diphenylcyclopropenone (diphencyprone, DPCP)
• immunotherapy
• melanoma
• Th17 cells

Disclaimer

The content of this review is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Financial & competing interest disclosure

This work was supported by research grants from the US NIH to DK Agrawal. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Contact-sensitizing agents such as diphencyprone (DPCP) and 2,4-dinitrochlorobenzene (DNCB) may be effective in eradicating thin cutaneous metastatic melanomas accompanied by sustained remission.

• The ability of contact-sensitizing agents to stimulate immunogenicity of systemic metastatic melanoma is in the realm of possibility, but is weakly supported by case report literature. These agents primarily exert a local cutaneous immunogenic response.

• A 2007 paper demonstrated improved prognosis in patients with stage III disease treated with combination DNCB and dacarbazine therapy, but the overall impact of contact-sensitizing agents on survival of patients with melanoma is undetermined.

• DPCP and DNCB initiate an allergic contact hypersensitivity mediated predominantly by CD8⁺ T-lymphocytes, with Th17 cells recently implicated in an important ancillary role.

• Th17 cells have been identified in numerous studies examining immune cell populations present during allergic contact hypersensitivity. When appropriately stimulated, they are effective destroyers of melanoma cells in tissue locally exposed to contact allergens.

• Contact-sensitizing agents may enhance local tumor immunity by stimulating a brisk response of tumor killing cells to the malignant region, and by supporting increased antigenicity of malignant cells, possibly by haptenation.

• Modification of tumor cells with a hapten may induce a cytotoxic T-cell response not only to the tumor antigen–hapten complex, but also to the tumor antigens themselves.

• The effectiveness of immune therapies such as DPCP or DNCB may be dependent largely on the underlying immune status of the host.